The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Perioperative Bridging Anticoagulation

in Patients with Atrial Fibrillation
James D. Douketis, M.D., Alex C. Spyropoulos, M.D., Scott Kaatz, D.O.,
Richard C. Becker, M.D., Joseph A. Caprini, M.D., Andrew S. Dunn, M.D.,
David A. Garcia, M.D., Alan Jacobson, M.D., Amir K. Jaffer, M.D., M.B.A.,
David F. Kong, M.D., Sam Schulman, M.D., Ph.D., Alexander G.G. Turpie, M.B.,
Vic Hasselblad, Ph.D., and Thomas L. Ortel, M.D., Ph.D.,
for the BRIDGE Investigators*​​

A BS T R AC T

BACKGROUND
It is uncertain whether bridging anticoagulation is necessary for patients with From St. Joseph’s Healthcare Hamilton
atrial fibrillation who need an interruption in warfarin treatment for an elective (J.D.D.) and the Department of Medicine
(J.D.D.) and Hamilton Health Science
operation or other elective invasive procedure. We hypothesized that forgoing Center (S.S., A.G.G.T.), McMaster Uni-
bridging anticoagulation would be noninferior to bridging with low-molecular- versity, Hamilton, ON, Canada; Hofstra
weight heparin for the prevention of perioperative arterial thromboembolism and North Shore–Long Island Jewish School
of Medicine, Manhasset (A.C.S.), and
would be superior to bridging with respect to major bleeding. Mount Sinai Medical Center, New York
(A.S.D.) — both in New York; Hurley
METHODS Medical Center, Flint, MI (S.K.); Univer-
sity of Cincinnati College of Medicine,
We performed a randomized, double-blind, placebo-controlled trial in which, after Cincinnati (R.C.B.); NorthShore Univer-
perioperative interruption of warfarin therapy, patients were randomly assigned sity HealthSystem, Evanston (J.A.C.),
to receive bridging anticoagulation therapy with low-molecular-weight heparin and Rush University Medical Center, Chi-
cago (A.K.J.) — both in Illinois; Universi-
(100 IU of dalteparin per kilogram of body weight) or matching placebo adminis- ty of Washington Medical Center, Seattle
tered subcutaneously twice daily, from 3 days before the procedure until 24 hours (D.A.G.); Veterans Affairs Loma Linda
before the procedure and then for 5 to 10 days after the procedure. Warfarin treat- Healthcare System, Loma Linda, CA
(A.J.); and Duke Clinical Research Insti-
ment was stopped 5 days before the procedure and was resumed within 24 hours tute (D.F.K., V.H.) and Department of
after the procedure. Follow-up of patients continued for 30 days after the procedure. Medicine (T.L.O.), Duke University Medi-
The primary outcomes were arterial thromboembolism (stroke, systemic embolism, cal Center, Durham, NC. Address reprint
requests to Dr. Ortel at Duke University
or transient ischemic attack) and major bleeding. Medical Center, Box 3422, Durham, NC,
27710, or at ­thomas​.­ortel@​­duke​.­edu.
RESULTS
* A complete list of investigators in the
In total, 1884 patients were enrolled, with 950 assigned to receive no bridging Bridging Anticoagulation in Patients who
therapy and 934 assigned to receive bridging therapy. The incidence of arterial Require Temporary Interruption of War-
farin Therapy for an Elective Invasive
thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging Procedure or Surgery (BRIDGE) study is
group (risk difference, 0.1 percentage points; 95% confidence interval [CI], −0.6 to provided in the Supplementary Appen-
0.8; P = 0.01 for noninferiority). The incidence of major bleeding was 1.3% in the dix, available at NEJM.org.
no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, This article was published on June 22, 2015,
0.20 to 0.78; P = 0.005 for superiority). at NEJM.org.

N Engl J Med 2015;373:823-33.

CONCLUSIONS DOI: 10.1056/NEJMoa1501035
In patients with atrial fibrillation who had warfarin treatment interrupted for an Copyright © 2015 Massachusetts Medical Society.

elective operation or other elective invasive procedure, forgoing bridging antico-

agulation was noninferior to perioperative bridging with low-molecular-weight
heparin for the prevention of arterial thromboembolism and decreased the risk of
major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the
National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.)
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 The n e w e ng l a n d j o u r na l of m e dic i n e

F
or patients with atrial fibrillation (available with the full text of this article at
who are receiving warfarin and require an NEJM.org) was designed by the steering com-
elective operation or other elective invasive mittee (see the Supplementary Appendix, avail-
procedure, the need for bridging anticoagulation able at NEJM.org, for a full list of trial personnel)
during perioperative interruption of warfarin and approved by the institutional review board
treatment has long been uncertain.1-3 Each year, at each participating clinical center. The Duke
this common clinical scenario affects approxi- Clinical Research Institute managed the study.
mately one in six warfarin-treated patients with The clinical coordinating center was responsible
A Quick Take is
available at atrial fibrillation.4,5 Warfarin treatment is typi- for study coordination, randomization, and dis-
NEJM.org cally stopped 5 days before an elective procedure tribution of the study drug. The data coordinat-
to allow its anticoagulant effect to wane; it is ing center was responsible for maintenance of
resumed after the procedure, when hemostasis the study database, data validation, and analy-
is secured, at which point 5 to 10 days of treat- ses. Eisai donated the dalteparin, and University
ment is required to attain therapeutic anticoagu- of Iowa Pharmaceuticals prepared the matching
lation.6,7 During the interruption of warfarin placebo. Eisai had no role in the design or con-
treatment, bridging anticoagulation therapy, typi- duct of the study, the analysis of the data, or the
cally with low-molecular-weight heparin, can be preparation of the manuscript. The steering
given to minimize the time that patients do not committee vouches for the completeness and ac-
have an adequate level of anticoagulation, with curacy of the data and analyses and for the fidel-
the intent of minimizing the risk of periopera- ity of this report to the trial protocol.
tive arterial thromboembolism, such as stroke.6
Multiple observational studies have assessed Patients
the timing and dosing of perioperative bridging
Patients were eligible to participate in the trial if
with low-molecular-weight heparin.8-15 However,
they were 18 years of age or older; had chronic
the fundamental question of whether bridging (permanent or paroxysmal) atrial fibrillation or
anticoagulation is necessary during periopera-flutter, confirmed by means of previous electro-
tive warfarin interruption has remained unan- cardiography or pacemaker interrogation (patients
swered.16-18 Because of the lack of evidence, with atrial fibrillation associated with valvular
practice guidelines have provided weak and in-disease, including mitral valve disease, were eli-
consistent recommendations regarding the need gible); had received warfarin therapy for 3 months
for bridging anticoagulation.19-21 or longer, with an international normalized ratio
Against this background, the Bridging Anti-
(INR) therapeutic range of 2.0 to 3.0; were un-
coagulation in Patients who Require Temporary dergoing an elective operation or other elective
Interruption of Warfarin Therapy for an Elective
invasive procedure that required interruption of
Invasive Procedure or Surgery (BRIDGE) trial was
warfarin therapy; and had at least one of the fol-
designed to address a simple question: in pa- lowing CHADS2 stroke risk factors: congestive
tients with atrial fibrillation, is heparin bridging
heart failure or left ventricular dysfunction, hyper-
needed during interruption of warfarin therapytension, age of 75 years or older, diabetes melli-
before and after an operation or other invasive
tus, or previous ischemic stroke, systemic embo-
procedure? We hypothesized that forgoing bridg-
lism, or transient ischemic attack. Patients were
ing altogether would be noninferior to bridging
not eligible if they had one or more of the fol-
with low-molecular-weight heparin for the pre-lowing: a mechanical heart valve; stroke, systemic
vention of perioperative arterial thromboembo-embolism, or transient ischemic attack within
lism and would be superior to bridging with the previous 12 weeks; major bleeding within the
regard to the outcome of major bleeding. previous 6 weeks; creatinine clearance of less
than 30 ml per minute; platelet count of less than
100×103 per cubic millimeter; or planned cardiac,
Me thods
intracranial, or intraspinal surgery. A complete
Study Design and Oversight list of the trial inclusion and exclusion criteria is
The BRIDGE trial was a randomized, double- provided in the Supplementary Appendix. All
blind, placebo-controlled trial. The protocol participants provided written informed consent.

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 Bridging Anticoagulation in Patients with Atrial Fibrillation

Warfarin Warfarin

Restart warfarin
Resume dalteparin or placebo within 24 hr
after the procedure in patients who underwent
a procedure associated with a low risk
of bleeding

Screening visit Stop warfarin Procedure

Resume dalteparin or placebo 48 to 72 hr
after the procedure in patients who underwent
a procedure associated with a high risk
of bleeding
Final
Dalteparin Dalteparin contact

Placebo Placebo

Start Stop Stop study

study study drug when
drug drug INR therapeutic

Restart study drug

−30 −5 −4 −3 −2 −1 0 1 2 3 4 5 30
Study Day

Figure 1. BRIDGE Study Design.

Screening visits occurred between 30 days and 5 days before the planned procedure, and randomization (R) occurred 5 days before the
procedure. Warfarin treatment was discontinued 5 days before the procedure, and administration of the study drug was initiated 3 days
before the procedure. It was recommended that the international normalized ratio (INR) be measured 1 day before the procedure; if the
INR was greater than 1.8, oral vitamin K (1.0 to 2.5 mg) was recommended; if the INR was 1.5 to 1.8, oral vitamin K was optional. If
the procedure or surgery was delayed up to 3 days, administration of the study drug was continued until 24 hours before the procedure.
Warfarin treatment was restarted on the evening of or the day after the procedure, and the study drug was restarted 12 to 24 hours after
a minor (or low-bleeding-risk) procedure and 48 to 72 hours after a major (or high-bleeding-risk) procedure. Administration of the study
drug was continued after the procedure until the INR was 2.0 or higher on one occasion. The final patient follow-up occurred 30 days after
the procedure. LMWH denotes low-molecular-weight heparin.

Procedures response system with a toll-free telephone num-

Patients were randomly assigned to receive
bridging anticoagulation therapy with daltepa-
rin sodium (100 IU per kilogram of body weight
administered subcutaneously twice daily) or to
receive no bridging therapy (i.e., a matching
subcutaneous placebo) from 3 days before the
procedure until 24 hours before the procedure
and then for 5 to 10 days after the procedure.
Randomization was stratified according to study
center either with the use of an interactive voice-
ber and access codes or through the Internet.
The study drugs were provided in identical vials.
The administration of study drug followed a
standardized perioperative management protocol
(Fig. 1). Warfarin treatment was stopped 5 days
before the procedure, and administration of the
study drug (dalteparin or matching placebo) was
started 3 days before the procedure. The last
preprocedure dose of dalteparin or placebo was
given in the morning approximately 24 hours

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 The n e w e ng l a n d j o u r na l
before the procedure.22,23 Warfarin treatment was
restarted on the evening of or the day after the
procedure, at the patient’s usual dose. Adminis-
tration of dalteparin or placebo was resumed 12
to 24 hours after a minor (or low-bleeding-risk)
procedure and 48 to 72 hours after a major (or
high-bleeding-risk) procedure.8,10 The designation
of a procedure as having a low or high bleeding
risk was guided by means of a classification
scheme (see Table S1 in the Supplementary Ap-
pendix), but the final determination of risk was
left to the investigator’s discretion. The patient
continued to take the study drug after the pro-
cedure until the INR was 2 or higher on one
occasion. Patients had follow-up encounters by
telephone weekly, with the final encounter 30 to
37 days after the procedure. Perioperative man-
agement of antiplatelet therapy was left to the
site investigator’s discretion.
Study Outcomes
All study outcomes were assessed by 37 days after
the procedure. The primary efficacy outcome
was arterial thromboembolism, including stroke
(ischemic or hemorrhagic), transient ischemic
attack, and systemic embolism, and the primary
safety outcome was major bleeding. The second-
ary efficacy outcomes were acute myocardial
infarction, deep-vein thrombosis, pulmonary em-
bolism, and death, and the secondary safety
outcome was minor bleeding. The definitions of
the outcomes are provided in the Supplementary
Appendix. All study outcomes were indepen-
dently and blindly adjudicated.
Statistical Analysis
The primary efficacy outcome was arterial throm-
boembolism at 30 days. The initial sample-size
estimates for arterial thromboembolism were
based on the results of contemporaneous cohort
studies, which suggested that the rate in the
bridging group would be 1.0%.8-10,24,25 We also
assumed that the rate in the no-bridging group
would be 1.0%. The primary analysis of efficacy
was a noninferiority analysis with a one-sided
test at the 0.025 level. The noninferiority margin
was set at 1.0%. We determined that the hypoth-
esis of inferiority would be rejected if the upper
boundary of the 95% confidence interval for the
difference in rates would be less than 1.0 percent-
age point. We prespecified that the 95% confi-
dence interval for the difference in event rates
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of m e dic i n e
would be calculated with the use of methods
based on Barnard’s test,26 because this test per-
mits the calculation of confidence intervals in
analyses with small sample sizes. The confi-
dence interval values were calculated with the
use of StatXact software, version 9 (Cytel).27
The primary safety outcome was major bleed-
ing at 30 days after the procedure. The null
hypothesis of no difference in the incidence of
major bleeding was tested with a two-sided test
at the 0.05 level. The expected bleeding rates
were 1.0% in the no-bridging arm and 3.0% in
the bridging arm. The P value was calculated
with the use of Fisher’s mid-P test, as implement-
ed in SAS software, version 9.3 (SAS Institute),
and the 95% confidence interval was a likelihood-
ratio confidence interval calculated with the same
version of SAS.
We calculated that a sample of 1641 patients
per group would give the study 80% power to
detect the noninferiority of no bridging therapy,
assuming a rate of arterial thromboembolism of
1.0% in each group and a noninferiority margin
of 1.0%, at a one-sided alpha level of 0.025 for
arterial thromboembolism and a two-sided alpha
level of 0.05 for bleeding. With a 10% allowance
for patients withdrawing from the study, the re-
quired sample size was 1813 per group. We cal-
culated that this sample size would also give the
study more than 99% power to detect the ex-
pected difference in bleeding rates.
After approximately 850 patients had been
enrolled, it was clear that the rate of arterial
thromboembolism, as assessed by investigators
who were unaware of the study-group assign-
ments, was less than 0.5%, and we determined
that a revised sample size of 2526 would provide
at least 90% power for each primary end point.
After 1720 patients were enrolled, the rate of
arterial thromboembolism was 0.46%, and the
bleeding rate was 2.3% in the entire population.
A revised sample size of 1882 was calculated on
the basis of the estimate that this would provide
nearly 90% power for the two primary end points.
R e sult s
Patients
As shown in Figure 2, we recruited 1884 patients
during the period from July 2009 through Decem-
ber 2014 at 108 sites in the United States and
Canada; 950 patients were assigned to the placebo
 Bridging Anticoagulation in Patients with Atrial Fibrillation

6585 Patients were screened

4701 Were excluded

544 Were withdrawn by physician
4155 Did not meet inclusion criteria or met
exclusion criteria
2 Had unknown reasons

1884 Were enrolled and underwent

randomization

950 Were assigned to receive placebo 934 Were assigned to receive dalteparin

32 Discontinued study 39 Discontinued study

23 Withdrew consent 31 Withdrew consent
3 Were lost to follow-up 3 Were lost to follow-up
2 Were withdrawn by 1 Was withdrawn by
principal investigator principal investigator
4 Had other reasons 4 Had other reasons
5 Died 4 Died

913 Completed the study 891 Completed the study

Figure 2. Screening, Randomization, and Follow-up.

(no-bridging) group, and 934 patients were as-
signed to receive bridging treatment with daltepa-
rin (bridging group). Table 1 shows the charac-
teristics of the patients at baseline. The mean
age of the patients was 71.7 years, and 73.4% of
patients were male; the mean body weight was
95.8 kg. The mean CHADS2 score (CHADS2 scores
range from 1 to 6, with higher scores indicating
a greater risk of stroke) was 2.3; 38.3% of pa-
tients had a CHADS2 score of 3 or higher. A total
of 34.7% of the patients were taking aspirin, and
7.2% were taking another antiplatelet drug.
Of the 1884 patients enrolled in the trial,
1722 actually underwent the anticipated proce-
dure (as-treated group), and 162 did not. The
categories and types of operations and proce-
dures that the participants underwent are shown
in Table S2 in the Supplementary Appendix. The
most common procedures were gastrointestinal
(44.0%), cardiothoracic (17.2%), and orthopedic
(9.2%). Overall, 89.4% of patients underwent a
procedure that was classified as minor (low bleed-
ing risk) according to the prespecified classifica-
tion; however, 69.1% were treated as having a
low bleeding risk by the site investigator.
Perioperative Anticoagulant Management
The mean (±SD) number of doses of study drug
administered was 5.0±1.1 before the procedure
and 16.0±7.9 after the procedure (Table 2). The
mean dose of dalteparin administered was
9093±2240 IU subcutaneously twice daily. Ad-
herence to the study-drug protocol, defined as
administration of 100% of protocol-specified
doses of study drug, was 86.5% before the pro-
cedure and 96.5% after the procedure.
Study Outcomes
Of the 1884 patients enrolled in the trial, 71
discontinued participation and did not provide
outcome data; therefore, data from 1813 patients
were available for the analysis (Fig. 2). At 30 days
after the procedure, the incidence of arterial
thromboembolism was 0.4% (four events among
918 patients) in the no-bridging group and 0.3%
(three events among 895 patients) in the bridging

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Baseline Characteristics of the Patients.*

No Bridging Bridging
Characteristic (N = 950) (N = 934)
Age — yr 71.8±8.74 71.6±8.88
Male sex — no. (%) 696 (73.3) 686 (73.4)
Race — no. (%)†
White 860 (90.5) 849 (90.9)
Nonwhite 88 (9.3) 82 (8.8)
Unknown 2 (0.2) 3 (0.3)
Weight — kg 96.2±24.87 95.4±23.50
CHADS2 score‡
Mean 2.3±1.03 2.4±1.07
Distribution — no. (%)
0 1 (0.1) 1 (0.1)
1 216 (22.7) 212 (22.7)
2 382 (40.2) 351 (37.6)
3 229 (24.1) 232 (24.8)
4 96 (10.1) 106 (11.3)
5 23 (2.4) 27 (2.9)
6 3 (0.3) 5 (0.5)
CHF or left ventricular dysfunction — no. (%) 289 (30.4) 310 (33.2)
Hypertension — no. (%) 833 (87.7) 806 (86.3)
Diabetes mellitus — no. (%) 390 (41.1) 382 (40.9)
Stroke — no. (%) 79 (8.3) 99 (10.6)
Transient ischemic attack — no. (%) 79 (8.3) 77 (8.2)
Mitral valve disease — no. (%) 165 (17.4) 142 (15.2)
Stenosis 19 (2.0) 10 (1.1)
Regurgitation 142 (14.9) 133 (14.2)
Prolapse 13 (1.4) 5 (0.5)
Myocardial infarction — no. (%) 138 (14.5) 155 (16.6)
Renal disease — no. (%) 108 (11.4) 92 (9.9)
Solid malignant disease — no. (%) 68 (7.2) 52 (5.6)
Laboratory values
Hemoglobin — g/dl 13.8±1.67 13.8±1.62
Platelet count — thrombocytes/mm3 209,300±592,900 209,200±580,500
INR 2.4±0.57 2.4±0.57
Serum creatinine — mg/dl 1.1±0.32 1.1±0.32
Creatinine clearance — ml/min 88.1±39.50 87.6±40.14
Medication use — no. (%)
Aspirin 324 (34.1) 329 (35.2)
Clopidogrel 30 (3.2) 21 (2.2)
Nonsteroidal antiinflammatory drug 34 (3.6) 25 (2.7)
COX-2 inhibitor 8 (0.8) 13 (1.4)

* Plus–minus values are means ±SD. There were no significant differences between the groups (P<0.05). CHF denotes
congestive heart failure, COX-2 cyclooxygenase type 2, and INR international normalized ratio.
† Race was self-reported. The patients for whom data were unknown are those who chose not to provide information.
‡ CHADS2 is a score used to estimate the risk of stroke in patients with atrial fibrillation. The score ranges from 1 to 6; 1
point each is assigned for congestive heart failure, hypertension, age of 75 years or older, and diabetes mellitus, and 2
points are assigned for stroke or transient ischemic attack.

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 Bridging Anticoagulation in Patients with Atrial Fibrillation

Table 2. Perioperative Anticoagulant Management.

No Bridging Bridging
Variable (N = 950) (N = 934) P Value
Warfarin treatment
Preprocedure time not taking warfarin 0.28
No. of patients with data 872 839
Mean — days 5.2±1.4 5.3±1.8
Time to first postprocedure warfarin dose 0.40
No. of patients with data 735 696
Mean — days 1.5±1.3 1.4±1.0
Low-molecular-weight heparin or placebo
Preprocedure dose 0.61
No. of patients with data 796 768
Mean no. of doses 5.0±0.7 5.0±1.4
Patients in whom the last dose was taken on the morning of 778/796 (97.7) 734/768 (95.6) 0.02
the day before the procedure — no./total no. (%)
Time to first postprocedure dose
Major surgery or procedure (high bleeding risk) 0.74
No. of patients with data 235 223
Mean — hr 53.3±31.6 51.3±27.9
Minor surgery or procedure (low bleeding risk) 0.74
No. of patients with data 526 497
Mean — hr 21.1±2.3 21.0±2.4
Postprocedure dose 0.47
No. of patients with data 764 721
Mean no. of doses 15.7±7.4 16.1±8.4
Aspirin treatment — no./total no. (%) 0.53
Interruption ≥7 days before procedure 92/324 (28.4) 92/329 (28.0)
Interruption <7 days before procedure 41/324 (12.7) 33/329 (10.0)
No interruption 191/324 (59.0) 204/329 (62.0)

group (mean between-group difference, 0.1 per-
centage points; 95% confidence interval [CI],
−0.6 to 0.8; P = 0.01 for noninferiority; P = 0.73
for superiority) (Table 3). In an as-treated analy-
sis, the rates of arterial thromboembolism were
0.3% (three events among 875 patients) in the
no-bridging group and 0.4% (three events
among 847 patients) in the bridging group
(mean between-group difference, 0.0 percentage
points; 95% CI, −0.7 to 0.7; P = 0.006 for noninfe-
riority). Patients in whom arterial thromboembo-
lism occurred had a mean CHADS2 score of 2.6
(range, 1 to 4), and five of the seven events oc-
curred after a minor procedure. The median
time to an arterial thromboembolism event after
the procedure was 19.0 days (interquartile range,
6.0 to 23.0).
Major bleeding occurred in 1.3% of the pa-
tients (12 of 918) in the no-bridging group and
in 3.2% (29 of 895) in the bridging group, which
indicated that no bridging was superior to bridg-
ing with regard to major bleeding (relative risk,
0.41; 95% CI, 0.20 to 0.78; P = 0.005). None of
the instances of major bleeding were fatal. For-
going bridging was associated with a risk of
minor bleeding that was significantly lower than
the risk associated with bridging (12.0% vs.
20.9%, P<0.001). The median time to a major
bleeding outcome after the procedure was 7.0
days (interquartile range, 4.0 to 18.0).

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 3. Study Outcomes.

ies involving a total of 12,278 patients with
atrial fibrillation or mechanical heart valves who
No Bridging Bridging received or did not receive bridging with low-
Outcome (N = 918) (N = 895) P Value
molecular-weight heparin showed no significant
number of patients (percent) difference in the rate of arterial thromboembo-
Primary lism (odds ratio with bridging, 0.80; 95% CI,
Arterial thromboembolism 4 (0.4) 3 (0.3) 0.01*, 0.73† 0.42 to 1.54) but a higher rate of major bleeding
Stroke 2 (0.2) 3 (0.3) (odds ratio, 3.60; 95% CI, 1.52 to 8.50) in asso-
ciation with bridging.28 In a substudy of the Ran-
Transient ischemic attack 2 (0.2) 0
domized Evaluation of Long-Term Anticoagula-
Systemic embolism 0 0
tion Therapy (RE-LY),29 in which patients with
Major bleeding 12 (1.3) 29 (3.2) 0.005† atrial fibrillation were randomly assigned to re-
Secondary ceive warfarin or dabigatran in an open-label
Death 5 (0.5) 4 (0.4) 0.88† manner, bridging anticoagulation was associat-
Myocardial infarction 7 (0.8) 14 (1.6) 0.10† ed with a rate of major bleeding that was higher
Deep-vein thrombosis 0 1 (0.1) 0.25† than that associated with no bridging (6.8% vs.
1.6%, P<0.001) among 1424 warfarin-treated
Pulmonary embolism 0 1 (0.1) 0.25†
patients who had treatment interruption for an
Minor bleeding 110 (12.0) 187 (20.9) <0.001†
elective procedure, and there was no significant
* P value for noninferiority. effect on arterial thromboembolism (0.5% vs.
† P value for superiority. 0.2%, P = 0.32).30 The Outcomes Registry for Bet-
ter Informed Treatment of Atrial Fibrillation study
(ORBIT-AF), which involved 2200 patients with
There was no significant difference between atrial fibrillation who required an elective proce-
the groups in the rates of acute myocardial in- dure, also showed a higher rate of bleeding if
farction, deep-vein thrombosis, pulmonary em- bridging anticoagulation therapy was used during
bolism, or death. Information on the causes of perioperative interruption of warfarin treatment.31
death and times to death is provided in Table S3 The rationale for the use of bridging anti­
in the Supplementary Appendix. coagulation therapy has been anchored on the
premise that the associated higher bleeding risk
was clinically acceptable because it would be off-
Discussion
set by a lower risk of perioperative arterial throm-
We found that in patients with atrial fibrillation boembolism.32 The findings from the BRIDGE
who require perioperative interruption of warfa- trial as well as from nonrandomized studies
rin treatment for an elective procedure, a strategy suggest that the perioperative risk of arterial
of discontinuing warfarin treatment without the thromboembolism in patients with atrial fibril-
use of bridging anticoagulation was noninferior lation during interruption of warfarin treatment
to the use of bridging anticoagulation for the pre- may have been overstated and may not be miti-
vention of arterial thromboembolism; in addi- gated by bridging anticoagulation. Indeed, the
tion, bridging conferred a risk of major bleeding mechanisms of perioperative arterial thrombo-
that was nearly triple the risk associated with no embolism may be more closely related to factors
bridging. There was also less minor bleeding such as the type of procedure33 and to intraop-
without bridging than there was with bridging, erative alterations in blood pressure.34 The prem-
and there was no significant difference between ise that warfarin interruption leads to rebound
the groups with regard to myocardial infarction, hypercoagulability and that the milieu of the
venous thromboembolism, or death. Taken to- procedure confers a prothrombotic state, which
gether, these findings show that there is a net in turn leads to arterial thromboembolism, is not
clinical benefit in favor of a strategy of forgoing supported by the results of this trial.35-37
bridging, as compared with perioperative bridg- There are potential limitations of the BRIDGE
ing with low-molecular-weight heparin. trial. First, although we aimed to recruit a repre-
The findings in our trial are consistent with sentative sample of patients with atrial fibrillation
those from nonrandomized comparisons of these for whom bridging anticoagulation is normally
strategies. A meta-analysis of observational stud- considered, certain groups were underrepresent-

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 Bridging Anticoagulation in Patients with Atrial Fibrillation
ed. Few patients had a CHADS2 score of 5 or 6,
although the mean score of 2.3 is similar to that
among patients with atrial fibrillation who were
assessed in recent trials and patient registries, in
which the mean scores were between 2.1 and
2.8.29,38-40 Patients undergoing major surgical
procedures associated with high rates of arterial
thromboembolism and bleeding (e.g., carotid
endarterectomy, major cancer surgery, cardiac
surgery, or neurosurgery)19,33 were not represented
in the trial, although the procedures performed
were representative of the most common inter-
ventions patients undergo during an interrup-
tion of therapeutic anticoagulation, the majority
of which are low-risk procedures, such as colo-
noscopy or ambulatory surgery.4,5,41 In addition,
the findings should not be applied to patients
with mechanical heart valves, who were specifi-
cally not included in the trial.
Second, the overall rate of arterial thrombo-
embolism was lower than expected, which po-
tentially affected the power of the trial to detect
a benefit associated with bridging. Although we
had expected perioperative arterial thromboem-
bolism rates to be approximately 1.0%,8,9,12,24 the
observed rate (0.4%) is similar to rates in recent
studies involving patients who had perioperative
interruption of warfarin treatment.4,5,31,42 In addi-
tion, the noninferiority margin we selected turned
out to be large in relation to the actual observed
event rate; it reflected the original estimate of
the event rate as specified in the trial protocol.
Third, the observed rate of major bleeding in
the bridging group (3.2%, with no instances of
fatal bleeding) may be considered to be modest.
However, our bridging protocol was designed to
minimize bleeding, and the higher rates of
bleeding reported in other studies of bridging
anticoagulation probably reflect resumption of
bridging therapy too soon after operations with
a high bleeding risk10,43 or a lack of standardized
bridging protocols.28,30
Fourth, the reduction in the study sample size
may raise concerns. This reduction was driven
by the lower rate of arterial thromboembolism
overall, with the proviso that power was main-
tained to address the primary study hypotheses.
Although extending the trial was considered,
this was not done because the added statistical
power would have been negligible and because
recruitment had been challenging throughout
the course of the trial.
Finally, one may contend that the trial find-
n engl j med 373;9 nejm.org  August 27, 2015
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Copyright © 2015 Massachusetts Medical Society. All rights reserved.
ings have diminished relevance because of the
decreasing use of warfarin in the treatment of
patients with atrial fibrillation, given the avail-
ability of the newer direct oral anticoagulants.6
However, warfarin remains widely used among
patients with atrial fibrillation.44-46 Furthermore,
the trial findings may also apply to the newer
agents. In the substudy of the RE-LY trial dis-
cussed above, dabigatran-treated patients who
had treatment interruption for an elective proce-
dure had more major bleeding with bridging
therapy than without bridging therapy, and there
was no significant effect on arterial thrombo-
embolism.30
In conclusion, in the BRIDGE trial, we found
that for patients with atrial fibrillation who re-
quire temporary interruption of warfarin treat-
ment for an elective operation or other elective
invasive procedure, a strategy of forgoing bridg-
ing anticoagulation was noninferior to periopera-
tive bridging with low-molecular-weight heparin
for the prevention of arterial thromboembolism.
The strategy of forgoing bridging treatment also
decreased the risk of major bleeding.
Supported by grants from the National Heart, Lung, and Blood
Institute for the clinical coordinating center (U01HL087229, to
Dr. Ortel) and for the data coordinating center (U01HL086755,
to Dr. Hasselblad). Eisai supplied the active drug, dalteparin
sodium (Fragmin), through an unrestricted investigator-initiated
grant to Dr. Ortel.
Dr. Douketis reports receiving fees for serving on advisory
boards from Biotie, Portola, and the Medicines Company, hono-
raria from Bristol-Myers Squibb, Pfizer, and Sanofi Aventis,
consulting fees from Boehringer Ingelheim, Bayer, Janssen,
Bristol-Myers Squibb, Daiichi-Sankyo, and Actelion, and grant
support from Boehringer Ingelheim; Dr. Spyropoulos, receiving
consulting fees from Janssen, Boehringer Ingelheim, Daiichi-
Sankyo, and Pfizer, and grant support from Daiichi-Sankyo; Dr.
Kaatz, receiving consulting and lecture fees from Boehringer
Ingelheim, Bristol-Myers Squibb/Pfizer Alliance, Janssen, CSL
Behring, and Daiichi-Sankyo, and grant support through his
institution from Boehringer Ingelheim, Bristol-Myers Squibb/
Pfizer Alliance, Janssen, Iverson Genetics Diagnostics/Medi-
care, and Blue Cross Blue Shield of Michigan; Dr. Becker, receiv-
ing fees for serving on scientific advisory boards from Janssen,
Portola, and Daiichi-Sankyo; Dr. Caprini, receiving fees for
serving on advisory boards from Bristol-Myers Squibb and Pfizer,
fees for serving on a steering committee from Janssen, and lec-
ture fees from Sanofi Aventis; Dr. Garcia, receiving consulting
fees from Pfizer, Genzyme, Boehringer Ingelheim, Bristol-Myers
Squibb, Portola, and Daiichi-Sankyo, and grant support from
Bayer; Dr. Jacobson, receiving consulting fees from Bristol-
Myers Squibb/Pfizer Alliance, Daiichi-Sankyo, Boehringer In-
gelheim, Janssen, Roche Diagnostics, and Alere, and lecture
fees from Bristol-Myers Squibb/Pfizer Alliance, Daiichi-Sankyo,
Boehringer Ingelheim, and Janssen; Dr. Jaffer, receiving con-
sulting fees from Pfizer, Janssen, Daiichi-Sankyo, Boehringer
Ingelheim, Marathon, and Medtronic; and Dr. Ortel, receiving
consulting fees from Instrumentation Laboratory, CSL Behring,
and Daiichi-Sankyo, and grant support from Instrumentation
Laboratory. No other potential conflict of interest relevant to
this article was reported.
831
 The n e w e ng l a n d j o u r na l of m e dic i n e

Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Andrei L. Kindzelski, who served as the National
Institutes of Health program official; Jill Lynch, University of
Iowa Pharmaceuticals, who was the manufacturer of the
matching placebo; and James Bernstein, Live Oak Pharmaceu-
ticals Consulting, for pharmacy consultancy regarding the
processes involved in the manufacture of the matching placebo
and for packaging the study drug kits for distribution to the
trial sites.

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